1. Field of the Invention
The present invention relates to 2-(N-substituted-aminoalkyl)-5-(E)-alkylidene cyclopentanones, 2-(N-substituted-aminoalkyl)-5-(E)-arylalkylidene cyclopentanones, and derivatives thereof and their use as anti-inflammatory, analgesic and anticancer agents.
2. Brief Description of the Prior Art
It is known that sesquiterpene lactones, such as, for example, Helenalin, Tenulin and Aromaticin, possess potent anti-inflammatory (T. G. Waddell et al., J. Pharm. Sci., 1979, 68:715; I. H. Hall et al., J. Pharm. Sci., 1980, 69:537) and anticancer (K. H. Lee et al., Cancer Res., 1971, 31:1649; S. M. Kupchan et al., J. Med. Chem., 1971, 14:1147) activities. S. M. Kupchan et al. demonstrated that the presence of an .alpha.-methylene-.gamma.-lactone was essential for significant anticancer activity among the sesquiterpene lactones. It has also been shown (G. A. Howie et al., J. Med. Chem., 1976, 19:309) that substitution of an alkyl group at the .alpha.-methylene carbon of .alpha.-methylene-.gamma.-lactone results in compounds of lower toxicity and higher selectivity. Furthermore, it was shown by I. H. Hall et al. that the .alpha.-methylene-.gamma.-lactone moiety within the structure of sesquiterpene lactones, specifically pseudoguaianolide and germacranolide derivatives, was required for activity against carrageenin induced edema inflammation.
While these natural products have potent activities, and a great deal of non-sesquiterpene lactones containing an .alpha.-methylene-.gamma.-lactone moiety have been identified and found active, they are unlikely to be of therapeutic value due to their low natural abundance and difficult chemical synthesis. Several attempts (J. M. Cassady et al., J. Med. Chem., 1978, 21:815; K. H. Lee et al., J. Med. Chem., 1978, 21:819) were made to simplify these structures for anticancer activity, but no successful results were obtained.
The prior art discloses several alkylidene and/or alkylamino substituted cyclopentanones and cyclopentenones.
U.S. Pat. No. 3,269,942 (Wilkes) discloses a method for the protection of aqueous media against slime-producing microorganisms which comprises adding to the aqueous media a selected 2,5-bis(N,N-dialkylaminomethyl)cyclopentanone compound. Unlike the present invention, Wilkes discloses no 5-(E)-alkylidene substituted cyclopentanones. Furthermore, Wilkes does not teach a pharmaceutical use for its compounds, but instead employs them for toxicity to slime-producing microorganisms.
U.S. Pat. No. 3,852,296 (Viterbo et al.) discloses selected 2,3-disubstituted Mannich bases of cyclopentanones and cyclopent-2-enones. The compounds are taught as having cholerectic, diuretic, anti-inflammatory and analgesic properties. Unlike the present invention, the compounds of Viterbo et al. have no 5-(E)-alkylidene group and have a substituent at position 3 of the ring.
U.S. Pat. No. 4,766,147 (Noyori et al.) discloses compounds modeled after prostoglandin A and prostoglandin E as pharmaceuticals for the treatment of tumors. The compounds include 5-alkylidene-4-substituted-2-cyclopentenones, 5-(1-hydroxy-aliphatic hydrocarbon)-4-substituted-2-cyclopentenones and 5-alkylidene-3-hydroxy-4-substituted cyclopentanones. Unlike the present invention, the compounds of Noyori et al. do not possess a Mannich base group.
U.S. Pat. No. 4,904,640 (Markert et al.) discloses 2-alkylidene-3,3,5 and 3,5,5-trimethylcyclopentanones as perfumes. Unlike the present invention, the compounds of Markert et al. do not possess a Mannich base group and are substituted at the 3-position of the ring. Furthermore, no pharmacological activity is taught for these compounds.
In spite of these prior disclosures, there remains a very real and substantial need for structurally simple synthetic compounds which maintain the potent anti-inflammatory and anticancer activity exhibited by the sesquiterpene lactones.